The spectrum of hereditary neuromuscular disorders in the Pakistani population.

Hereditary neuromuscular disorders (NMDs) are a broad group of clinically heterogeneous disorders with varying inheritance patterns, that are associated with over 500 implicated genes. In the context of a highly consanguineous Pakistani population, we expect that autosomal recessive NMDs may have a higher prevalence compared with patients of European descent. This is the first study to offer a detailed description of the spectrum of genes causing hereditary NMDs in the Pakistani population using NGS testing. To study the clinical and genetic profiles of patients presenting for evaluation of a hereditary neuromuscular disorder. This is a retrospective chart review of patients seen in the Neuromuscular Disorders Clinic and referred to the Genetics Clinic with a suspected hereditary neuromuscular disorder, between 2016 and 2020 at the Aga Khan University Hospital, Karachi and Mukhtiar A. Sheikh Hospital, Multan, Pakistan. The genetic testing for these patients included NGS-based single gene sequencing, NGS-based multi-gene panel and whole exome sequencing. In a total of 112 patients studied, 35 (31.3%) were female. The mean age of onset in all patients was 14.6 years (SD ±12.1 years), with the average age at presentation to the clinic of 22.4 years (SD ±14.10 years). Forty-seven (41.9%) patients had a positive genetic test result, 53 (47.3%) had one or more variants of uncertain significance (VUS), and 12 (10.7%) had a negative result. Upon further genotype-phenotype correlation and family segregation analysis, the diagnostic yield improved, with 59 (52.7%) patients reaching a diagnosis of a hereditary NMD. We also report probable founder variants in COL6A2, FKTN, GNE, and SGCB, previously reported in populations that have possible shared ancestry with the Pakistani population. Our findings reemphasizes that the rate of VUSs can be reduced by clinical correlation and family segregation studies.

Human serum N-glycome profiling via the newly developed asparagine immobilized cellulose/polymer nanohybrid.

Human serum N-linked glycans expression levels change during the disease progression. The low abundance, structural diversity, and coexisting matrices hinder their detection in mass spectrometry analysis. Considering the hydrophilic nature of N-glycans, cellulose/polymer (1,2-Epoxy-5-hexene) nanohybrid is fabricated with oxirane groups functionalized of asparagine to develop solid phase extraction based hydrophilic interaction liquid chromatography sorbent (cellulose/1,2-Epoxy-5-hexene/asparagine). The morphology, elemental analysis, and surface properties are studied through scanning electron microscopy, energy dispersive X-ray spectroscopy, and Fourier-transform infrared spectroscopy. The large surface area of cellulose/polymer nanohybrid (2.09 × 102  m2 /g) facilitates the high density of asparagine immobilization resulting in better hydrophilic interaction liquid chromatography enrichment under optimized conditions. The enrichment capability of nanohybrid/asparagine is assessed by the N-Linked glycans released from ovalbumin and immunoglobulin G where 23 and 13 N-glycans are detected respectively. The nanohybrid/asparagine shows selectivity of 1:1200 with spiked bovine serum albumin and sensitivity down to 100 attomole. Human serum profiling for N-glycans identifies 52 glycan structures. This new enrichment strategy enriches serum N-linked glycans in the presence of salts, proteins, endogenous serum peptides, and so forth.

Terpolymeric platform with enhanced hydrophilicity via cysteic acid for serum intact glycopeptide analysis.

A new polymeric (methyl methacrylate/ethylene glycol dimethacrylate/1,2-epoxy-5-hexene) base/matrix has been fabricated and decorated with zwitterionic hydrophilic cysteic acid (Cya) for the enrichment of intact N-glycopeptides from standards and biological samples. Terpolymer-Cya provides good enrichment efficiency, improved hydrophilicity, and selectivity by virtue of better surface area (2.09 × 102 m2/g) provided by terpolymer and the zwitterionic property offered by cysteic acid. Cysteic acid-functionalized polymeric hydrophilic interaction liquid chromatography (HILIC) sorbent enriches 35 and 24 N-linked glycopeptides via SPE (solid phase extraction) mode from tryptic digests of model glycoproteins, i.e., immunoglobulin G (IgG) and horseradish peroxidase (HRP), respectively. Zwitterionic chemistry of cysteine helps in achieving higher selectivity with BSA digest (1:200), and lower detection limit down to 100 attomoles with a complete glycosylation profile of each standard digest. The recovery of 81% and good reproducibility define the application of terpolymer-Cya for complex samples like a serum. Analysis of human serum provides a profile of 807 intact N-linked glycopeptides via nano-liquid chromatography-tandem mass spectrometry (nLC-MS/MS). To the best of our knowledge, this is the highest number of glycopeptides enriched by any HILIC sorbent. Selected glycoproteins are evaluated in link to various cancers including the breast, lung, uterine, and melanoma using single-nucleotide variances (BioMuta). This study represents the complete idea of using an in-house developed strategy as a successful tool to help analyze, relate, and answer glycoprotein-based clinical issues regarding cancers.

Iminodiacetic acid (IDA)-generated mesoporous nanopolymer: a template to relate surface area, hydrophilicity, and glycopeptides enrichment.

A three-step strategy is introduced to develop inherent iminodiacetic (IDA)-functionalized nanopolymer. SEM micrographs show homogenous spherical beads with a particle size of 500 nm. Further modification to COOH-functionalized 1,2-epoxy-5-hexene/DVB mesoporous nanopolymer enriches glycopeptides via hydrophilic interactions followed by their MS determination. Significantly high BET surface area 433.4336 m2 g-1 contributes to the improved surface hydrophilicity which is also shown by high concentration of ionizable carboxylic acids, 14.59 ± 0.25 mmol g-1. Measured surface area is the highest among DVB-based polymers and in general much higher in comparison to the previously reported BET surface areas of co-polymers, terpolymers, MOFs, and graphene-based composites. Thirty-one, 19, and 16 N-glycopeptides are enriched/identified by nanopolymer beads from tryptic digests of immunoglobulin G, horseradish peroxidase, and chicken avidin, respectively, without additional desalting steps. Material exhibits high selectivity (1:400 IgG:BSA), sensitivity (down to 0.1 fmol), regeneration ability up to three cycles, and batch-to-batch reproducibility (RSD > 1%). Furthermore, from 1 µL of digested human serum, 343 N-glycopeptide characteristics of 134 glycoproteins including 30 FDA-approved serum biomarkers are identified via nano-LC-MS/MS. The developed strategy to self-generate IDA on polymeric surface with improved surface area, porosity, and ordered morphology is insignia of its potential as chromatographic tool contributing to future developments in large-scale biomedical glycoproteomics studies.

Boronic acid functionalized MOFs as HILIC material for N-linked glycopeptide enrichment.

Highly specific enrichment of N-linked glycopeptides from complex biological samples is crucial prior to mass spectrometric analysis. In this work, a hydrophilic metal-organic framework composite is prepared by the growth of UiO-66-NH2 on graphene sheets, followed by its post-synthetic modification to attach boronic acid to form GO@UiO-66-PBA. The fabrication of graphene oxide-MOF composite results in enhanced surface area with improved thermal and chemical stability. The synthesized MOF nanocomposite is characterized by scanning electron microscopy (SEM), transmission electron microscopy (TEM), X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR) and BET. A crystalline structure with high porosity offering large surface area and good hydrophilicity of the nanocomposite assists as an enrichment tool in glycoproteomics. The GO@UiO-66-PBA nanocomposite selectively enriches N-linked glycopeptides from tryptic digests of horseradish peroxidase (HRP) and immunoglobulin (IgG). GO@UiO-66-PBA nanoparticles show a low detection limit (1 fmol) and good specificity (1:200), reusability and reproducibility for N-linked glycopeptide enrichment from IgG digest. The binding capacity of GO@UiO-66-PBA is 84 mg/g for protein concentration, with a good recovery of 86.5%. A total of 372 N-linked glycopeptides corresponding to different glycoproteins are identified from only 1 µL of human serum digest. Thus, the presented research work can be an efficient separation platform for N-linked glycopeptide enrichment from complex samples, which can be extended to cost-effective routine analysis. Graphical abstract.

Highly porous terpolymer-ZIF8@BA MOF composite for identification of mono- and multi-glycosylated peptides/proteins using MS-based bottom-up approach.

A hydrophilic terpolymer MOF composite is designed with high surface area and porosity to enrich mono- and multi-glycosylated peptides facilitating a bottom-up approach. Terpolymer@ZIF-8 is synthesized using free radical polymerization followed by layer by layer ZIF-8 fabrication. Subsequent surface modification was made by aminophenylboronic acid (AMBA). The enrichment ability of terpolymer@ZIF-8@BA is evaluated by using tryptic digest of IgG and HRP to exemplify mono- and multi-glycosylated protein samples. Improved selectivity of 1:200 for spiked HRP in BSA digest and sensitivity down to 1 fmol µL-1 is achieved. Batch to batch reproducibility is better 1% RSD which favors the adoption of the developed method for routine N-linked glycopeptide/protein determination. Cost-effective nature of given approach is given by regeneration of the material up to four cycles. Total 318 N-linked glycopeptides have been identified from 1 µL human serum digest after subjecting the enriched and PNGase-treated deglycosylated peptides to LC-MS. Thus, terpolymer@ZIF-8@BA holds the potential both for mono- and multi-glycosylated peptides from complex biological sample. Graphical abstract.

Metal-organic framework-based affinity materials in proteomics.

Metal-organic frameworks (MOFs) are an eminent addition to materials science research because of their versatile properties due to which their applications are wide spread in proteomics. They are used in various fields due to their characteristics like higher surface area, specific symmetry, ease of modification, and availability of a variety of ligands. As affinity sorbents, they have shown higher selectivity, sensitivity, and reproducibility than conventionally used materials. They are applied for the enrichment of phosphopeptides, glycopeptides, low mass peptides, and as laser desorption/ionization (LDI) matrices for small-molecule analysis. This review captures the insight of applying MOFs in the field of mass spectrometry-based proteomics. The specific features are discussed regarding MOFs as affinity sorbents for the selective capture of biological molecules like phosphopeptides and glycopeptides from complex samples. The potential of MOFs as LDI mass spectrometry (LDI-MS) matrices for small-molecule analysis is also evaluated. MOFs have also been used as enzymatic reactors for the digestion of proteins, prior to MS analysis. MOF-based affinity materials and bioreactors reduce proteome complexity and improve detection sensitivity and coverage. Size-exclusion effects of MOFs help in subtracting the abundant proteins in peptidomics. Several limitations of MOFs are addressed, which include stability under varying pH conditions, the unclear interaction mechanism between the MOFs and targeted analytes, and the non-specific binding that interferes during the analysis because of metal centers and ligands in the MOFs. This will open up MOF-based research to overcome the limitations and improve the performance of MOFs as selective and sensitive materials. Graphical abstract ᅟ.

Carcinogenesis of PIK3CA.

PIK3CA is the most frequently mutated oncogene in human cancers. PIK3CA is phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha. It controls cell growth, proliferation, motility, survival, differentiation and intracellular trafficking. In most of human cancer alteration occurred frequently in the alpha isoform of phosphatidylinositol 3 kinase. PIK3CA mutations were most frequent in endometrial, ovarian, colorectal, breast, cervical, squamous cell cancer of the head and neck, chondroma, thyroid carcinoma and in cancer family syndrome. Inhibition of PI3K signaling can diminish cell proliferation, and in some circumstances, promote cell death. Consequently, components of this pathway present attractive targets for cancer therapeutics. A number of PI3K pathway inhibitors have been developed and used. PI3K inhibitors (both pan-PI3K and isoform-specific PI3K inhibitors), dual PI3K-mTOR inhibitors that are catalytic site inhibitors of the p110 isoforms and mTOR (the kinase component of both mTORC1 and mTORC2), mTOR catalytic site inhibitors, and AKT inhibitors are the most advanced in the clinic. They are approved for the treatment of several carcinomas.

Delta brush on EEG: a characteristic EEG finding in autoimmune encephalitis.

A woman in her late 20s was admitted via the emergency department in the psychiatric ward with acute-onset behavioural changes and suicidal thoughts in the past 2 weeks. Workup revealed positive N-methyl-D-aspartate (NMDA) receptor antibodies in cerebrospinal fluid and electroencephalogram (EEG) showing a specific pattern of delta brush on bilateral frontal regions. Other investigations were unremarkable. The patient was started on intravenous methylprednisolone 1000 mg for 5 days with oral steroids. She responded on steroids. She has been recommended for workup for teratoma/mediastinal tumours with NMDA receptor encephalitis is an autoimmune disorder predominantly affecting women of childbearing age. Delta brush pattern on EEG is specific for NMDA receptor encephalitis hence can be used as a diagnostic tool. It is advisable to investigate any patient with the presentation of mental deterioration for pathological causes. However, treatment with immunotherapy increases the chance of survival and may prevent cognitive impairment.

Mapping the low abundant plasma glycoproteome using Ranachrome-5 immobilized magnetic terpolymer as improved HILIC sorbent.

HILIC (hydrophilic interaction liquid chromatography) materials enrich glycopeptides. The non-specific interactions because of support material and inadequate hydrophilicity render loss of less abundant glycopeptides in SPE-based enrichments. In this work, magnetic terpolymer (Fe3O4@MAA/DVB/1,2-Epoxy-5-hexene) is functionalized with Ranachrome-5 to generate enhanced hydrophilicity. Amine, carboxylic, and amide groups of ranachrome-5 provide zwitterionic chemistry. Material's magnetic core contributes to ease of operation while higher surface area 97.0711 m2 g-1 immobilizes better quantities of Ranachrome-5. Homogeneous morphology, nano-size, and super hydrophilicity enhance enrichment. Ranachrome-5 functionalized polymeric core-shell beads enrich 25, 18 and 16 N-linked glycopeptides via SPE strategy from tryptic digests of model glycoproteins i.e., immunoglobulin G (IgG), horseradish peroxidase (HRP) and chicken avidin, respectively. Zwitterionic chemistry of ranachrome-5 helps in achieving higher selectivity (1:250, HRP / Bovine Serum Albumin), and lower detection limit (100 attomole, HRP digest) with complete glycosylation profile of each standard digest. High binding capacity (137.1 mg/g) and reuse of affinity material up to seven cycles reduce the cost and amount of affinity material for complex sample analysis. A recovery of 91.76% and relative standard deviation (RSD) values less than 1 define the application of HILIC beads for complex samples like plasma. 508 N-linked intact low abundant glycopeptides corresponding to 50 glycoproteins are identified from depleted human plasma samples via nano-Liquid Chromatography-Tandem Mass Spectrometry (nLC-MS/MS). Using Single Nucleotide Variances (BioMuta) for low abundant plasma glycoproteins, the potential association of proteins to four cancers, i.e., breast, lung, uterine, and melanoma is evaluated. Via the bottom-up approach, HILIC beads can analyze clinically important low-abundant glycoproteins.

Spectrum of EEG Abnormalities in COVID-19 Patients.

PURPOSE: Neurologic involvement is commonly reported in coronavirus disease (COVID-19) patients. The published literature regarding the COVID-19-related neurophysiological findings, including the EEG findings, is still quite limited. The objective of this study was to evaluate the EEG findings in patients with a COVID-19 infection and look for a possible correlations and prognosis. METHODS: This is an inpatient hospital-based retrospective observational study. All admitted COVID-19 patients undergoing an EEG study between January 1, 2020 and June 30, 2021 were included in this study. EEG was ordered by the primary intensive care physician or a neurologist taking part in the clinical care of patients. RESULTS: Sixty-six EEG studies in 57 patients were included. Mean age was 62.2 ± 16.3 years with male predominance (65%). Encephalopathy (70%) was the most common indication for an EEG. Background EEG abnormalities were seen in most of the patients (92.4%) with severe abnormalities correlating with the prognosis of the patient. Epileptiform discharges were only seen in 7.5% of the EEGs, with majority of the discharges arising from the frontal region. Mortality reported was high (47%). CONCLUSIONS: Nonspecific diffuse background EEG abnormalities are commonly seen in COVID-19 patients. Epileptiform discharges are less common but mostly originate from frontal region. Most of these patients also had an abnormal neuroimaging. The significance of this peculiar finding needs further research. SIGNIFICANCE: Nonspecific background EEG changes are common in COVID-19 patients. Among epileptiform discharges, focal epileptiform discharges arising from the frontal region were common, usually associated with an abnormal neuroimaging.

Steroid-Responsive Myositis Associated With Acute Hepatitis E Infection.

Acute hepatitis E virus (HEV) infection is usually self-limiting and presents as mild jaundice accompanied by malaise, anorexia, nausea, vomiting, abdominal pain, or fever. Rarely, it can lead to fulminant hepatic failure especially in pregnant women or cause extrahepatic manifestations. We report a case of a young woman already diagnosed with acute HEV infection who presented with a generalized body rash and weakness in all four limbs. She was subsequently diagnosed with inflammatory myositis and treated successfully with steroids. We have reviewed relevant literature for a possible association. Myositis is a rare but known complication of HEV. If timely diagnosed and managed, there is a significant reduction in morbidity.

Harmful effects of shisha: literature review.

Tobacco is a preventable cause of morbidity and mortality across the world. A recently infamous way of smoking tobacco is shisha. Shisha smoking is also known as water pipe, hookah and Narghile smoking. The percentage of shisha smokers is on the rise rapidly spanning the globe. A literature review was conducted to identify all evidence on the epidemiological variations and health effects of shisha smoking. "Pub med" is used as a searching tool to identify all relevant empirical studies conducted worldwide. A qualitative overview of evidence is presented. Exposure to Shisha smoking is significantly associated with low infant weight, heart rate variations, hyperglycemia and hypertriglyceridemia. Increased risk of carcinoma is also leagued with it including carcinomas of the pancreas and lung being at the forefront. In conclusion, this review identifies grounds of several adverse conditions being associated with the habit of shisha smoking. It also evaluates the relevant epidemiological variations around the globe. The review culminates in the importance of enlightening shisha smokers regarding its deleterious effects.

Magnetic Resonance Image findings of Spinal Tuberclosis at first presentation.

BACKGROUND: Spinal tuberculosis presents in various pathological patterns. The clinical presentation and often the management depend on exact pathological findings. Objective of study was to evaluate the Pathology of spinal tuberculosis as depicted by MRI findings in 119 consecutive cases of spinal TB. METHODOLOGY: It was a cross sectional and observational study conducted at Civil Hospital, Karachi from July 2010 to December 2012.Total numbers of participants were 119. Diagnosis was based on positive histopathology results along with the supportive evidence in MRI. A pre-structured questionnaire was constructed to record the data. Study was ethically approved by Institutional Review Board of Dow University of Health Sciences. Sample size was calculated by using Open-EPI software. All the data was entered and analyzed through SPSS 19. RESULT: There were 119 patients who participated in this study out of which 52 were males and 67 were females. Most common level was Dorso-lumbar (33.6%) and 87.5% of them had spondylodiscitis while 90% had cord compression. All 6 (100%) patients who had their upper- dorsal region affected had gibbus formation while all those patients having lumbosacral region involved had thecal compression 4 (100%). Most common mode of treatment used in patients having Spinal TB at Lumbar region was conservative (86.2%). CONCLUSION: MRI findings were mostly shadowed with features such as disc destruction and thecal or cord compression. MRI scan could be used for early detection of spinal TB which can reduce disability and deaths in patients. Major clinical findings in spinal TB were fever, Para paresis and back pain.

"Risk factors of birth asphyxia".

BACKGROUND: Birth asphyxia is an insult to the fetus or newborn due to failure to breath or breathing poorly, leads to decrease oxygen perfusion to various organs. According to WHO, 4 million neonatal deaths occurred each year due to birth asphyxia. Our goal was to evaluate antepartum, intrapartum, and fetal risk factors of birth asphyxia. METHODS: It was a Retrospective Case control study, conducted at Neonatal Intensive Care Unit of pediatric ward (I, II, III) and in Gynecology wards (I, II, III) of Civil Hospital Karachi, Dow University of Health Sciences. Study was conducted from January 2011-November 2012. Neonates diagnosed with birth asphyxia were considered as "cases" while neonates born either with normal vaginal delivery or by cesarean section having no abnormality were considered as "control". Demographics of both the mother and neonate were noted and Questions regarding possible risk factors were asked from mother. Ethical issues were confirmed from Institutional review board of Civil Hospital Karachi, Dow University of Health Sciences. All data was entered and analyzed through SPSS 19. RESULT: Out of total 240 neonates, 123 were "cases" and 117 were "control". Mean maternal age in "case" group was 24.22 ± 3.38 while maternal age of control group was 24.30 ± 4.04. Significant antepartum risk factors were maternal age of 20-25 (OR 0.30 CI 95% 0.07-1.21), booking status (OR 0.20 CI 95% 0.11-0.37), pre-eclampsia (OR 0.94 CI 95% 0.90-0.98) and primigravidity (OR 2.64 CI 95% 1.56-4.46). Significant Intrapartum risk factors were breech presentation (OR 2.96 CI 95% 1.25-7.02), home delivery (OR 16.16 CI 95% 3.74-69.75) and maternal fever (OR 10.01 CI95% 3.78-26.52). Significant Fetal risk factors were resuscitation of child (OR 23 CI 95% 31.27-1720.74), pre-term babies(OR 0.34 CI 95% 0.19-0.58), fetal distress (OR 0.01 CI 95% 0.00-0.11) and baby weight (OR 0.13 CI 95% 0.05-0.32). CONCLUSION: Measures should be taken to prevent neonatal mortality with great emphasis on skilled attendance at birth and appropriate care of preterm and low birth weight neonates.

Spectrum of prostatic lesions.

BACKGROUND: Prostate gland of male reproductive system is about the size of walnut and surrounds the urethra. Most frequently encountered diseases affecting prostate are Prostatitis, Benign prostatic hyperplasia and Prostatic cancer .Our objective of study was to evaluate the spectrum and correlation of prostatic lesions with presenting complaints of patient. METHODS: It was a cross-sectional study conducted in Pathology Department of Dow Medical College, Dow University of Health Sciences during the period of 1st January 2010 to December 2012. Pathology department of Dow Medical College collected specimens from both Civil Hospital and Lyari General Hospital Karachi, Pakistan. Specimens were taken through transurethral resection of prostate (TURP), simple prostatectomy and radical prostatectomy. A questionnaire was made and information including name, age, ward name of hospital, laboratory number, clinical diagnosis and symptoms were noted in it. Data was entered and analyzed through SPSS 19. RESULT: During the targeted months, 48 prostatic specimens were received with a mean age of 65.7 + -7.6 years. Common presenting complains were urinary retention in 23(47.9%) patients, followed by dribbling in 12(25%). Out of 48 patients, 42 have Benign Prostatic Hyperplasia and 6 have Prostatic Adenocarcinoma. Both Benign Prostatic Hyperplasia and Prostatic Adenocarcinoma were more prevalent in the age group of 60-70 years. CONCLUSION: Frequency of prostatic cancer is on the rise and measures should be taken for its early detection. Screening protocols and awareness programs need to be introduced. Screening programs should be focused on level of androgens and molecular pathogenesis.

Clinico- pathological profile of patients with breast diseases.

BACKGROUND: To evaluate the spectrum of breast diseases and their association with presenting complains of patients. METHODOLOGY: It was a cross sectional study conducted from 1st January 2010 - 30th December 2012. A total of 254 breast specimens of patients, who were admitted in Civil Hospital Karachi with breast complaints, were included. Specimens were collected either from mastectomy, lumpectomy or needle biopsy from the admitted patients. Informed written consent was taken from all the patients. All patients with primary breast diseases were included. Patients undergoing chemotherapy or with secondary breast disease and slides with insufficient specimen were excluded. All data was entered and analyzed through SPSS 19. RESULT: There were 254 breast lesions, histologically diagnosed in 3 year review period. The overall mean age of patients with breast lesion was 25.18, SD ± 11.73 with a wide age range of 12-74 years. Most common cases identified are benign 191(75.3%), followed by inflammatory 30(11.8%) and malignant lesions 30(11.8%). Most patients presenting with the complain of pain have diagnosis of fibroadenoma 24 (63.2%) while patient with complain of lump also have the most common diagnosis of fibroadenoma 147 (72.8%). CONCLUSIONS: Study shows that in Pakistani females, mostly encountered breast lesion was fibroadenoma. Due to lack of awareness breast diseases present lately. Awareness must be created among women to reduce the mortality and morbidity with breast lesions. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1037059088969395.

c-Met inhibitors.

c-Met is a receptor tyrosine kinase that encodes protein such as hepatocyte growth factor receptor (HGFR). Inappropriate activity of c-Met can cause wide variety of carcinomas. c-Met inhibitor are relatively new class of small molecules that inhibit the enzymatic activity of c-Met tyrosine kinase. Met inhibitors divided into two main classes: class I (SU-11274-like) and class II (AM7-like). The use of c-Met inhibitors with other therapeutic agents could be crucial for overcoming potential resistance as well as for improving overall clinical benefit. Met pathway inhibitors might be used in combination with other treatments, including chemo-, radio- or immunotherapy.

Bcr-Abl tyrosine kinase inhibitors- current status.

Bcr-Abl plays a central role in the development of chromosome positive leukaemia. Chronic Myeloid leukaemia occurs due to increase proliferation and resistance to apoptosis by Bcr-Abl positive cells. Imatinib (STI571) is the first drug in the family of Bcr-Abl tyrosine kinase inhibitors while Nilotinib (AMN107) and Dasatinib (BMS-345825) are second generation drugs that are intended to have less resistance and intolerance than imatinib. Ponatinib (AP24534) an orally active Bcr-Abl Tyrosine Kinase Inhibitor and Bafetinib (INNO-406) have efficacy against various point mutations in the Bcr-Abl kinase. 1, 3, 4 thiadiazole derivatives has also displayed moderate inhibitory action on both Abl and Src kinase family. However there are varieties of Bcr-Abl inhibitors but Nilotinib is still the frontline tyrosine kinase inhibitors.